Triazine compounds for treatment of CNS disorders

ABSTRACT

A compound of formula (I)and pharmaceutically acceptable prodrugs, salts and solvates thereof.

This application is a division of application Ser. No. 09/582,058, filedJul. 12, 2000, the entire content of which is hereby incorporated byreference in this application which is a 371 of PCT/EP98/08273 filed onDec. 12, 1998.

The present invention relates to a triazine compound which is useful inthe treatment of central nervous system (CNS) diseases and disorders andto its pharmaceutically acceptable derivatives, to pharmaceuticalcompositions containing them, to their use in the treatment of suchdisorders and to methods of preparation.

EP-A-0021121 and EP-A-0247892 describe 3,5-diamino triazines, forexample 3,5diamino-6-(2,3dichlorophenyl)-1,2,4-triazine (lamotrigine),which are active in the treatment of disorders of the CNS and areparticularly useful in the treatment of epilepsy.

The present invention relates to a 5-amino triazine derivative which isa sodium channel blocker. This compound is a surprisingly potentanti-convulsant having increased potency with respect to lamotrigine andincreased selectivity in terms of CNS side-effects and inhibition of theenzyme dihydrofolate reductase. The compound is therefore useful in thetreatment of CNS diseases such as epilepsy.

Accordingly, the invention provides a compound of formula (I)

i.e. 5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine andpharmaceutically acceptable derivatives thereof.

By pharmaceutically acceptable derivative is meant any pharmaceuticallyacceptable salt or solvate of the compounds of formula (1), or any othercompound which upon administration to the recipient is capable ofproviding (directly or indirectly) a compound of formula (I) or anactive metabolite or residue thereof (eg. a prodrug). Referencehereinafter to the compounds of formula (I) includes the compound offormula (I) and pharmaceutically acceptable derivatives thereof.

Suitable pharmaceutically acceptable salts of the compound of formula(I) include acid addition salts formed with inorganic or organic acids,preferably inorganic acids, e.g. hydrochlorides, hydrobromides andsulphates.

Suitable prodrugs are well-known in the art and include N-acylderivatives, for example at either of the four nitrogens in thecompounds of formula (I), for example simple acyl derivatives such asacetyl, propionyl and the like or groups such as R—O—CH₂-nitrogen orR—O—C(O)-nitrogen.

The compounds of formula (I) are particularly useful as anticonvulsants.They are therefore useful in treating epilepsy. They may be used toimprove the condition of a host, typically a human being, suffering fromepilepsy. They may be employed to alleviate the symptoms of epilepsy ina host “Epilepsy” is intended to include the following seizures: simplepartial seizures, complex partial seizures, secondary generalisedseizures, generalised seizures including absence seizures, myoclonicseizures, clonic seizures, tonic seizures, tonic clonic seizures andatonic seizures.

The compounds of formula (I) are additionally useful in the treatment ofbipolar disorder, alternatively known as manic depression. Type I or IIbipolar disorder may be treated. The compounds of formula (I) may thusbe used to improve the condition of a human patient suffering frombipolar disorder. They may be used to alleviate the symptoms of bipolardisorder in a host. The compounds of formula (I) may also be used in thetreatment of unipolar depression.

The compounds of formula (I) are useful as analgesics. They aretherefore useful in treating or preventing pain. They may be used toimprove the condition of a host, typically a human being, suffering frompain. They may be employed to alleviate pain in a host. Thus, thecompounds of formula (I) may be used as a preemptive analgesic to treatacute pain such as musculoskeletal pain, post operative pain andsurgical pain, chronic pain such as chronic inflammatory pain (eg.rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. postherpetic neuralgia, trigeminal neuralgia and sympathetically maintainedpain) and pain associated with cancer and fibromyalgia. The compounds offormula (I) may also be used in the treatment or prevention of painassociated with migraine.

The compounds of formula (I) are further useful in the treatment offunctional bowel disorders which include non-ulcer dyspepsia, noncardiac chest pain and in particular irritable bowel syndrome. Irritablebowel syndrome is a gastrointestinal disorder characterised by thepresence of abdominal pain and altered bowel habits without any evidenceof organic disease. The compounds of formula (I) may thus be used toalleviate pain associated with irritable bowel syndrome The condition ofa human patient suffering from irritable bowel syndrome may thus beimproved.

The compounds of formula (I) may also be useful in the treatment ofneurodegenerative diseases, such as Alzheimer's disease, ALS, motorneuron disease, Parkinson's disease, muscular sclerosis, maculardegeneration and glaucoma. The compounds of formula (I) may also beuseful in neuroprotection and in the treatment of neurodegenerationfollowing stroke, cardiac arrest, pulmonary bypass, traumatic braininjury, spinal cord injury or the like.

The compounds of formula (I) are further useful in the treatment oftinnitus.

Still further, the compounds of formula (I) are also useful inpreventing or reducing dependence on, or preventing or reducingtolerance or reverse tolerance to, a dependence inducing agent. Examplesof dependence inducing agents include opioids (eg morphine), CNSdepressants (eg ethanol), psychostimulants (eg cocaine) and nicotine.

There is therefore further provided by the present invention, use of acompound of formula (I) or a pharmaceutically acceptable derivativethereof for use in human and veterinary medicine.

There is therefore further provided by the present invention, use of acompound of formula (I) in the manufacture of a medicament for use inthe treatment of a disorder substantially as hereinbefore described.

The present invention further comprises a method of treating a patientsuffering from, or susceptible to, a disorder substantially ashereinbefore described, which method comprises administering to thepatient a therapeutically effective amount of a compound of formula (I).

The term “treatment” as used herein includes the treatment ofestablished disorders, and also includes the prophylaxis thereof

The precise amount of the compounds of formula (I) administered to ahost, particularly a human patient, will be the responsibility of theattendant physician However, the dose employed will depend upon a numberof factors including the age and sex of the patient, the precisecondition being treated and its severity, and the route ofadministration.

The compound of formula (I) may be administered at a dose of from 0.1 to10 mg/kg body weight per day and more particularly 0.3 to 3 mg/kg bodyweight per day, calculated as the free base. The dose range for adulthuman beings is generally from 8 to 1000 mg/day, such as from 35 to 800mg/day, preferably 10 to 200 mg/day or 20 to 200 mg/day, calculated asthe free base.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are conveniently administered in the form of pharmaceuticalcompositions. Thus, in another aspect of the invention, we provide apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable derivative thereof adapted for use in humanor veterinary medicine. Such compositions may conveniently be presentedfor use in conventional manner in admixture with one or morephysiologically acceptable carriers or excipients.

While it is possible for the compounds of formula (I) to be administeredas the raw chemical, it is preferable to present it as a pharmaceuticalformulation. The formulations of the present invention comprise thecompounds of formula (I) thereof together with one or more acceptablecarriers or diluents therefor and optionally other therapeuticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing into association the compound of formula (I) or apharmaceutically acceptable acid addition salt thereof (“activeingredient”) with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tablets(e.g. chewable tablets in particular for paediatric administration) eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as a solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, hard fat or polyethyleneglycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose and acacia.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

Preferred unit dosage formulations are those containing an effectivedaily dose, as herein above recited, or an appropriate fraction thereof,of the active ingredient. Conveniently that may be from 5 mg to 1000 mg,such as from 8 mg to 1000 mg, more conveniently 35 mg to 800 mg, andmost conveniently 10 to 200 mg or 20 to 200 mg, calculated as the freebase.

The compounds of formula (I) may be used in combination with othertherapeutic agents, for example other anticonvulsants. When compounds offormula (I) are used in combination with other therapeutic agents, thecompounds may be administered either sequentially or simultaneously byany convenient route. The invention thus provides, in a further aspect,a combination comprising a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof with a further therapeutic agent.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease, the dose of each compound maydiffer from that when the compound is used alone. Appropriate doses willbe readily appreciated by those skilled in the art.

The present invention provides a process for preparing compounds offormula (I) and pharmaceutically acceptable derivatives thereof.

The compounds of formula (I) may be prepared by the methods outlinedbelow which form a further aspect of the invention.

According to a general process (A), which forms a further aspect of theinvention, a compound of formula (I) may be prepared under suitablereaction conditions from a compound of formula (II)

for example, by reduction, preferably using a reduction metal, such asRaney nickel, and a source of hydrogen, such as hydrazine monohydrate,in a suitable solvent, such as ethanol, preferably at elevatedtemperature, for example between 70-750° C.

According to another process (B), which forms a further aspect of theinvention, a compound of formula (I) may be prepared under suitablereaction conditions by reacting a compound of formula (III)

wherein n may be one or two, with a reducing agent. Suitable reducingagsents include borohydrides, preferably sodium borohydride. Thereaction may be carried out in a solvent mixture, such as an ether,preferably tetrahydrofuran and an alcohol, preferably t-butanol and atroom temperature.

A compound of formula (III) may be prepared under suitable reactionconditions by reacting a compound of formula (II) with an oxidisingagent, such as a peracid, for example potassium peroxymonosulfate orm-chloroperbenzoic acid and at a reduced temperature, for example, <5°C. and this forms a further aspect of the invention.

A compound of formula (II) may suitably be prepared by reacting2,3,5-trichlorobenzoyl cyanide with a S-methylthiosemicarbazide salt,preferably hydroiodide, in the presence of a dilute mineral acid,preferably dilute sulphuric acid and this forms a further aspect of theinvention.

A compound of formula (II) may alternatively be prepared under suitablereaction conditions by the photolysis of a solution of a compound offormula (IV), at between 320 and 750 nm

in a suitable solvent, such as an alcohol, preferably propan-1-ol and atelevated temperature, for example the reflux temperature of the solventand this forms a further aspect of the invention.

2,3,5-trichlorobenzoyl cyanide and S-methylthiosemicarbazide may beprepared according to conventional procedures and this forms a furtheraspect of the invention.

A compound of formula (IV) may be prepared under suitable reactionconditions by reacting a compound of formula (V)

with a dehydrating agent, preferably diphosphoryl chloride and thisforms a further aspect of the invention.

A compound of formula (V) may suitably be prepared by the reaction of acompound of formula (VI)

with a S-methylthiosemicarbazide salt, preferably hydroiodide, in asuitable solvent, for example ethanol, and at elevated temperature, forexample 50° C. and this forms a further aspect of the invention.

A compound of formula (VI) may be prepared under suitable reactionconditions by reacting 2,3,5-trichlorobenzoyl cyanide with a strongaqueous acid, preferably concentrated hydrochloric acid, which forms afurther aspect of the invention.

Prodrugs of the compounds of formula (I) may be prepared according toconventional procedures.

The following Examples which should not be construed as constituting alimitation thereto are provided to illustrate the invention.

Intermediate 1

2,3,5-Trichlorobenzoic Acid

2,3,5-Trichlorobenzaldehyde (197.40 g, 0.94 mole, Lancaster) wasdissolved in t-butanol (785 ml), stirred and heated under nitrogen at50° C. 2M Aqueous sodium hydroxide (940 ml) was warmed to 50° C. andadded to the solution of the aldehyde. Hydrogen peroxide (27.50%aqueous, 699 g, 5.65 mole) was added using a dosing pump over 45 min,maintaining the temperature between 57-60° C. The reaction mixture wasthen stirred and heated under nitrogen for a further hour, cooled andevaporated in vacuo. The residual slurry was filtered and the filtratewas washed with toluene (2×300 ml) and then acidified (pH1) with 5Mhydrochloric acid whilst stirring vigorously. The resulting thick whiteprecipitate was filtered, washed with water (3×300 ml) and dried invacuo at 50° C. Yield 180 g (85%). M.p. 155-158° C. (froth).

Intermediate 2

2,3,5-Trichlorobenzoyl Chloride

2,3,5-Trichlorobenzoic acid (75 g, 0.33 mole, Example 1) and thionylchloride (197.47 ml, 271.32 g, 2.28 mole) were refluxed in anhydroustoluene (350 ml) at 120° C. for 3 hrs. The reaction mixture was cooledto room-temperature and evaporated in vacuo. The residue was azeotropedwith anhydrous toluene (3×100 ml) to give a brown viscous oil.

An alternative preparation can be carried out as follows:

2,3,5-Trichlorobenzoic acid (75 g, 333 mmol, 1 eq) was added to toluene(225 ml) and the slurry was heated at reflux for 2 hours with adean-stark apparatus attached. The acid dissolved into the solution uponheating. The solution was cooled with good stirring, and pyridine (0.2ml, cat.˜0.5 mol %) and thionyl chloride (26.7 ml, 365 mmol, 1.1 eq)were added via a dropping funnel over a period of 1 hour, maintaining aninternal temperature between 70-80° C. Once the addition was complete,the mixture was heated at reflux for 2 hours. The solution was cooled,the volatiles were removed in vacuo, and then azeotroped with toluene(2×50 ml) to give a clear yellow oil as the product.

Intermediate 3

2,3,5-Trichlorobenzoyl Cyanide

Copper (I) cyanide (63.88 g, 0.71 mole), potassium iodide (108.20 g,0.65 mole) were refluxed in anhydrous xylene (590 ml) at 150° C. for 24hrs using Dean-Stark apparatus. A solution of 2,3,5-trichlorobenzoylchloride in anhydrous xylene (150 ml) was added and the resultingsuspension was refluxed under nitrogen at 150° C. for 3 days. Thesuspension was filtered and the filtrate was evaporated in vacuo.δ(CDCl₃): 7.80 (s, 1H), 8.0 (s, 1H).

An alternative preparation can be carried out as follows:

Potassium iodide (66.25 g, 400 mmol, 1.2 eq) (sieved to particle size <1mm) and copper (I) cyanide (36 g, 400 mmol, 1.2 eq), in xylene (400 ml)were heated at reflux for 3 hours with a dean-stark apparatus attached.The mixture was cooled, and 2,3,5-trichlorobenzoyl chloride, in xylene(100 ml), was added. The mixture was heated at reflux with a dean-starkapparatus attached. The mixture gradually turned red/orange over 30minutes, and a light brown solution was obtained overnight.

The mixture was heated at reflux for 40 hours, then cooled, and theinorganics filtered off. The xylene was removed in vacuo a @ 55° C.,azeotroped with toluene (2×50 ml), then petroleum ether 60-80 (260 ml)was added via a buchi inlet, to give a brown solution. On cooling, abrown precipitate was formed. The solution was stirred at roomtemperature overnight, the solid filtered off, and washed with petroleumether 60-80 (100 ml). The solid was sucked dry under nitrogen blanket toafford a first crop of yellow solid, 2,3,5-trichlorobenzoyl nitrile(45.5 g, 58.1%).

The filtrate was concentrated, left to stand for 24 hours, and a secondcrop was then collected (6.8 g, 8.7%), followed by a third crop (5.3 g,6.8%). Total yield (57.6 g, 73.8%). N.m.r.(d₆-DMSO) dppm: 8.03(d,1H),8.34(d, 1H).

Intermediate 4

S-Methylthiosemicarbazide Hydroiodide

Thiosemicarbazide (448 g, 0.50 mole, Aldrich) and iodomethane (300 ml, 5mole) were refluxed in 95% ethanol (2000 ml ) for 5 hrs and then cooledto room-temperature. The desired product was filtered, washed with ether(3×300 ml) and dried in vacuo. Yield 647 g. M.p. 138-140° C.

Intermediate 5

3-Thiomethyl-5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine [Formula(II)]

Route A

S-Methylthiosemicarbazide hydroiodide (38.59 g, 0.17 mole) was suspendedin dilute sulphuric acid (95.83 ml concentrated sulphuric acid/95.83 mlwater) and stirred at room-temperature for one hour. A solution of2,3,5-trichlorobenzoyl cyanide (18 g, 0.077 mole) in acetonitrile (90ml) was slowly added and the resulting mixture was stirred atroom-temperature for eleven days. The reaction mixture was diluted withwater and extracted with ethylacetate (3×250 ml) The ethylacetate layerwas washed with water (2×300 ml), dried over anhydrous magnesiumsulphate, filtered and evaporated the filtrate in vacuo The residue wasdissolved in propan-1-ol (500 ml) and refluxed at 130° C. for 4 hrs. Thereaction mixture was cooled to room-temperature and evaporated in vacuo.The residue was partitioned between 2N aqueous sodium hydroxide(100 ml)and ethylacetate (300 ml). The ethylacetate layer was washed with water(2×100 ml), dried over anhydrous magnesium sulphate, filtered andevaporated the filtrate in vacuo. The residue was purified by ‘flashchromatography’ using cyclohexane to 1:3 cyclohexane:ether as theeluent. Yield 1.90 g (8%) M.p. 138-140° C.

Route B

2-[S-Methylthiosemicarbazono]-2-[2,3,5-trichlorophenyl]-acetonitrile(1.00 g, 3.11 mmol) was stirred in propan-1-ol (40 ml) and heated toreflux under nitrogen. A 300 Watt tungsten lamp was shone onto themixture and the reaction left under these conditions for forty-eighthours. The reaction was cooled to room temperature, then the lamp wasswitched off and the solution evaporated in vacuo to leave a dark oilwhich crystallised on standing. The solid was triturated with methanol,filtered and dried to give product,3-thiomethyl-5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine. Yield 770mg (77.0%). N.M.R. (d₆-DMSO) δ ppm: 2.50(s, 3H), 7.15(broad s, 1H),7.63(d, 1H), 7.90(broad s, 1H), 8.00(d, 1H). LC/MS, Electrospraypositive (M+1)⁺=321/323.

Intermediate 6

3-Methylsulfoxy-5amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine [Formula(III)]

3-Thiomethyl-5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine (6 g, 18.7mmol, 1 eq), was suspended in dichloromethane (650 ml), and cooled to 5°C. m-Chloroperbenzoic acid (5.669, 18.7 mmol, assumed 57%, ˜1 eq) wasadded in one portion and stirred at <10° C. for 20 minutes, undernitrogen, resulting in a clear yellow solution. Analysis by TLC (1:1cyclohexane ethyl acetate) showed no remaining starting material. Thereaction was quenched by the addition of sodium sulfite (10 g) and water(200 ml) to the vigourous stirred solution. The layers were separatedand the organic layer was washed with 10% aqueous sodium sulfitesolution (100 ml). Merck peroxide test strips were found to be negative.The organic layer was washed with saturated sodium hydrogen carbonate(200 ml), then washed with a brine solution (200 ml), and then driedover anhydrous magnesium sulfate. The organic solution was filtered andthe solvent was removed in vacuo to afford a yellow solid,3-Methylsulfoxy-5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine. Yield5.82 g (92.2%).

N.m.r.(CDCl₃) δ ppm: 3.05(s,3H), 7.39(d,1H), 7.69(d,1H). LC/MSElectrospray positive (M+1)⁺=337/339.

Intermediate 7

2-Oxo-2-[2,3,5-trichlorophenyl]-acetamide [Formula (VI)]

2,3,5-Trichlorobenzoyl cyanide (10.0 g, 46 mmole) was added toconcentrated hydrochloric acid (140 ml) and stirred at room temperaturefor forty-eight hours. The suspension was diluted with water (100 ml)and then filtered. The light-brown solid was washed with water, thenair-dried for one hour. The crude product was then dissolved in ethylacetate (400 ml), washed with saturated aqueous sodium hydrogencarbonate solution (2×300 ml), followed by brine (300 ml) and then driedover magnesium sulphate, filtered and evaporated to leave a beige solid.This solid was triturated in hexaneltoluene (200 ml), filtered and driedin vacuo, to yield an off-white solid,2-oxo-2-[2,3,5-trichlorophenyl]-acetamide. Yield 7.02 g (65.3%). N.M.R.(d₆-DMSO) δ ppm: 7.77(d, 1H), 8.09(d, 1H), 8.13(broad s, 1H), 8.48(broads, 1H). LC/MS, Electrospray negative (M−1)⁻=250/252.

Intermediate 8

2-[S-Methylthiosemicarbazono]-2-[2,3,5-trichlorophenyl]-acetamide[Formula (V)]

2-Oxo-2-[2,3,5-trichlorophenyl]-acetamide (5.00 g, 19.8 mmol) andS-methylthiosemicarbazide hydroiodide (9.20 g, 39.5 mmol) were suspendedin ethanol (100 ml) and heated at 50° C., under nitrogen, overnight. Asthin layer chromatography showed the starting material was stillpresent, a further quantity of S-methylthiosemicarbazide hydroiodide(4.00 g, 17.2 mmol) was added and stirring was continued at 50° C. fortwo hours. The reaction mixture was evaporated in vacuo to yield a brownoil. This oil was dissolved in ethyl acetate (400 ml), washed with water(300 ml), then brine (300 ml), dried over magnesium sulphate, filteredand evaporated in vacuo to afford a yellow-brown gum. This gum waspurified by column chromatography using 1:1 ethyl acetate:hexane as theeluent. The product, predominantly the E isomer, was obtained as a paleyellow solid, yield 4.25 g (63.2%). N.M.R. (d₆-DMSO) δ ppm: 2.14(s,3H),7.28(d,1H), 7.31(broad s,1H), 7.84(d,1H), 8.28(broad s,1H). LC/MS,Electrospray positive (M+1)⁺=339/341.

Intermediate 9

2-[S-Methylthiosemicarbazono]-2-[2,3,5-trichlorophenyl]-acetonitrile[Formula (IV)]

2-[S-Methylthiosemicarbazide]-2-[2,3,5-trichlorophenyl]-acetamide (2 g,5.89 mmol) was added portionwise to a solution of diphosphoryl chloride(2.97 g, 1.63 ml, 11.8 mmol) in 1,4-dioxane (16 ml) and stirred undernitrogen for six hours. The dark solution was evaporated in vacuo toleave a dark-yellow oil. The oil was dissolved in ethyl acetate (50 ml),washed with water (50 ml), saturated aqueous sodium hydrogen carbonate(50 ml), brine (50 ml), then dried over magnesium sulphate, filtered andevaporated in vacuo to give a dark-yellow oil The crude product waspurified by column chromatography using 3:1 hexane:ethyl acetate as theeluent. The product,2-[S-Methylthiosemicarbazono]-2-[2,3,5-trichlorophenyl]-acetonitrile wasobtained as a yellow oil which crystallised to a yellow solid uponstanding. Yield 1.16 g (61.2%). N.M.R. (d₆-DMSO) δ ppm: 2.20(s,1H),3.38(broad s,3H), 7.68(broad s,1H), 7.95(d,1H), 8.12(broad s, 1H).LC/MS, Electrospray positive (M+1)⁺=321/323.

EXAMPLE 5-Amino-6-[2,3,5-trichlorophenyl]1,2,4-triazine

Process A

Raney nickel (3.50 g, suspension in water, Fluka) was suspended in asolution of 3-thiomethyl-5-amino-6-(2,3,5trichlorophenyl)-1,2,4-triazine(1.75 g, 5.44×10⁻³ mole) in absolute ethanol (30 ml) and stirred at 70°C. Hydrazine monohydrate (3.50 ml, 3.54 g, 0.11 mole) was added dropwiseto the suspension over 30 min. The resulting mixture was stirred at70-75° C. for 2 hours filtered, washed with hot absolute ethanol (3×20ml) and the filtrate evaporated in vacuo. The residue was purified by‘flash chromatography’ using 15:25 cyclohexane:ether to ether as theeluent and then by Preparative Hplc using Supelcosil ABZ column and 50%acetonitrile/water and 0.1% formic acid as the eluent. Yield 0.134 g(9%) M.p. 220-222° C., R_(t)=13.691 min, N.m.r.(d₆-DMSO) δ ppm: 6.90(Broad, s,1H), 7.60 (d,1H), 7.70 (Broad, s,1H), 8.0 (d, 1H), 8.70 (s,1H). LC/MS (EI) M⁺=275/277.

Process B

3-Methylsulfoxy-5-amino-6-[2,3,5-trichlorophenyl]-1,2,4triazine (5.82 g,17.2 mmol, 1 eq) was dissolved in a 1:1 mixture of THF:t-butanol (1800ml). Sodium borohydride (915 g, 24.08 mmol, ˜1.4 eq) was added in oneportion and the resulting mixture was stirred at room temperature, undernitrogen, for 2 hours. All solvent was removed in vacuo to give a yellowsolid which was then azeotroped with tetrahydrofuran (200 ml). 10%Aqueous citric acid (500 ml) was added slowly keeping the temperaturebelow 20° C., followed by ethyl acetate (500 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate(500 ml). Th combined organic layers were washed with saturated brine,dried over anhydrous magnesium sulfate, filtered and any volatiles wereremoved in vacuo to give a yellow solid.

The product was purified using column chromatography, using 20% ethylacetate in hexane as the eluent, increasing to 60% ethyl acetate inhexane. Product-containing fractions were combined and evaporated invacuo, affording a yellow solid,5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine. Yield 1.5 g (31.7%).

N.m.r.(d₆DMSO) δ ppm: 7.67(d,1H), 8.02(d,1H), 8.75(s,1H),7.0-7.2(broads, 1H),7.7-8.0(broad s,1H). LC/MS Electrospray positive (M+1)⁺=275/277

PHARMACY EXAMPLES

Sterile Formulations

Example A

mg/ml Compounds of the Invention 0.1 mg Sodium Chloride USP 9.0 mg Waterfor Injection USP qs to 1 ml

The components are dissolved in a portion of the water for injectionsand the solution made up to a final volume to provide 0.1 mg/ml of thecompounds of the Invention. Where a salt of the compounds is used, thequantity of compounds is increased to provide 0.1 mg/ml of the freebase. The solution may be packaged for injection, for example by fillingand sealing into ampoules, vials or syringes. These may be asepticallyfilled and/or terminally sterilised by, for example, autoclaving at 121°C.

Further sterile formulations may be prepared in a similar manner toobtain alternative concentrations of the compounds.

Example B

mg/ml Compounds of the Invention 0.5 mg Mannitol 50.0 mg Water forInjections qs to 1.0 ml

Dissolve the components in a portion of the Water for Injections. Makeup to final volume and mix until homogeneous. Filter formulation througha sterilising filter and fill into glass vials. Lyophilise and sealvials. Reconstitute with appropriate solvent prior to use.

Formulations for Oral Administration

Tablets may be prepared by the normal methods such as direct compressionor wet granulation. The tablets may be film coated with suitable filmforming materials, such as an Opadry, using standard techniques.Alternatively the tablets may be sugar coated.

Example C

Direct Compression Tablet mg/Tablet Compounds of the Invention 5.0 mgMagnesium Stearate 4.0 mg Microcrystalline Cellulose( Avicel PH102) qsto 400.0 mg

The compounds of the Invention are passed through a 30 mesh sieve andblended with the Avicel and Magnesium Stearate. The resultant blend iscompressed into tablets using a suitable tablet press fitted with 11.0mm diameter punches so as to provide 5 mg of the Compounds of theInvention per tablet. Tablets of other strengths, containing for example25 or 100 mg/tablet of the Compounds of the Invention may be prepared ina similar manner.

Example D

Wet Granulation Tablet mg/Tablet Compounds of the Invention 5.0 mgPregelled Starch 28.0 mg Sodium Starch Glycollate 16.0 mg MagnesiumStearate 4.0 mg Lactose qs 400.0 mg

The Compounds of the Invention, Lactose, Pregelled Starch and SodiumStarch Glycollate were dry mixed and then granulated using a suitablevolume of Purified Water. The resultant granules were dried and thenblended with the Magnesium Stearate. The dried granules were compressedusing a suitable tablet press fitted with 11.0 mm diameter punches so asto provide 5 mg of the Compounds of the Invention per tablet.

Tablets of other strengths such as 25 and 100 mg/tablet were prepared.

Example E

Hard Gelatin Capsule mg/capsule Compounds of the Invention 5.0 mgMicrocrystalline Cellulose (Avicel PH102) qs 700.0 mg

The Compounds of the Invention are passed through a 30 mesh sieve andthen blended with the Microcrystalline Cellulose to provide anhomogeneous blend The blend may then be filled into size 0EL hardgelatin capsule shells so as to provide capsules containing 5.0mg/capsule of Compounds of the Invention. Alternative strengths such as25 or 100 mg/capsule of Compounds of the Invention may be made in asimilar manner.

Example F

Soft Gelatin Capsule mg/capsule Compounds of the Invention 10.0 mgPolyethylene Glycol 90.0 mg Propylene Glycol qs 200.0 mg

Blend together the Polyethylene Glycol and Propylene Glycol using heatas necessary. Stir until homogeneous. Add the Compounds of the Inventionand mix until homogeneous. Fill into an appropriate gelatin mass to givesoft gelatin capsules containing 200 mg of the formulation, to provide10.0 mg/capsule of the Compounds of the Invention.

Alternative strengths for example, 5 and 25 mg/capsule of the Compoundsof the Invention may be prepared in a similar manner.

Example G

Syrup Compounds of the Invention 5.0 mg Sorbitol Solution 1500.0 mgGlycerol 1000.0 mg Sodium Benzoate 5.0 mg Flavour 12.5 mg Purified Waterqs to 5.0 ml

The Sodium Benzoate is dissolved in a portion of the purified water andthe Sorbitol Solution added. The Compounds of the Invention, Flavour andGlycerol are added and mixed until homogeneous. The resultant mixture ismade up to volume with the purified water.

Other Formulations

Example H

Suppository mg/suppository Compounds of the Invention 10.0 mg WitepsolW32, hard fat qs 2000.0 mg

Melt the Witepsol W32 at approximately 36° C. To a portion of this addthe Compounds of the Invention and blend. Incorporate the remainingmelted Witepsol W32 and blend until homogeneous. Fill mould with 2000 mgof the formulation to provide 10.0 mg/suppository of the Compounds ofthe Invention.

Example I

Transdermal Compounds of the Invention 5.0 mg Silicone Fluid 90.9 mgColloidal Silicone Dioxide 5.0 mg

Mix the silicone fluid and active together and add the colloidalsilicone dioxide. The material is then dosed into a subsequently heatsealed polymeric laminate comprised of the following: polyester releaseliner, skin contact adhesive composed of silicone or acrylic polymers, aa control membrane which is a polyolefin (for example polyethylene orpolyvinyl acetate) or polyurethane, and an impermeable backing membraneof a polyester multilaminate.

Biological Data

Activity Against voltage-gated Sodium Channels

Whole-cell voltage-clamp techniques were employed to evaluate theactivity of a compound of formula (I) on the recombinant human braintype IIA Na⁺ channel expressed in Chinese hamster ovary cells A compoundof formula (I) inhibits these channels in a voltage- and use-dependentmanner with an estimated K_(i) value of 11 μM for the steady-stateinactivation state, approximately 70-fold greater than the potency atthe resting state (IC₅₀=785 μM).

The increased state selectivity and greater use-dependent inhibitioncompared to lamotrigine (approximately 30-fold) provides a mechanismthrough which a compound of formula (I) selectively blocks transmissionduring high frequency firing of action potentials (e.g. seizureactivity). This supports the finding that a compound of formula (I) is amore potent anti-convulsant than lamotrigine and with a greatertherapeutic index.

Anticonvulsant Activity

A compound of formula (I) has been shown to have anti-epileptic activityin two rodent models of generalised epilepsy, the rat maximalelectroshock test (MES) which is an animal model that reflects humangeneralised tonic-clonic seizures and the mouse pentylenetetrazolinfusion test predictive of human absence seizures and myoclonic petitmal epilepsy.

For example, male Han Wistar rats (150-200 grms) were dosed orally witha suspension of the test compound in 0.25% methylcellulose 2 hr prior totest. A visual observation is carried out just prior to testing for thepresence of ataxia. Using auricular electrodes a current of 200 mA,duration 200 millisec, is applied and the presence or absence of hindlimb extension noted. A compound of formula (I) exhibited an ED₅₀ of 1.7mg/kg compared to 6.1 mg/kg for lamotrigine with a therapeutic index(ratio of the ataxia ED₅₀ and MES ED₅₀) of 23.7 compared to 3.3 forlamotrigine.

A compound of formula (I) exhibited an ED₅₀ of 3.8 mg/kg in the mousepentylenetetrazol infusion test (time to second twitch) when dosed 1 hrpost PTZ, compared to an ED₅₀ of 8.4 mg/kg for lamotrigine.

Analgesic Activity

A compound of formula (I) has also been shown to have analgesic activityin models of pain. Three hours after intraplantar carrageenanadministration (100 μl of 2%) in the rat there is a reduction in weightbearing on the inflamed paw and an increase in paw volume consistentwith acute hyperalgesia and inflammation. A compound of formula (I),administered orally 30 minutes prior to carrageenan, produced adoserelated inhibition of the carrageenan-induced reduction in weightbearing with an ED₅₀ of 7.5 mg/kg compared to 23.5 mg/kg forlamotrigine. A compound of formula (I) also showed significantanti-inflammatory activity in this model at 30 mg/kg (50% reduction inpaw volume).

Activity Against MPTP Induced Neurotoxicity

The mouse MPTP model is generally used as a model of Parkinson'sdisease.

Male C57BL/6 mice received four intraperitoneal injections of MPTP.HCl(15 mg of free base per kg; Research Biochemicals) in saline at 2 hourintervals. Control mice received saline only. The test-compound wasadministered as four subcutaneous injections in olive oil at 2 hourintervals, 30 minutes before each MPTP injection.

Seven days after MPTP injection the mice were sacrificed and the striatadissected out, immediately frozen, and stored at −80° C. until analysis.On the day of assay issue samples were sonicated in 10 volume (wt./vol.)of 0.1 M perchloric acid containing 1.9 mM sodium hydrosulfite and 1.6mg/ml DBA-HBr. After centrifugation (2800 g, 10 min at room temperature)and filtration (pore size 0.5 μm, Millipore), the supernatant wastransferred to a vial and placed in the automatic sampler (M231XL,Gilson). Dopamine content was measured by high performance liquidchromatography. A compound of formula (I) produced 75% protectionagainst dopamine depletion when dosed at 3 mg/kg (×4) and 98% protectionwhen dosed at 10 mg/kg (×4).

What is claimed is:
 1. A method of treating a patient suffering from, orsusceptible to epilepsy by administration of an effective amount of acompound of formula (I)

and salts thereof.
 2. A method of treating a patient suffering from, orsusceptible to bipolar disorder by administration of an effective amountof a compound of formula (I)

and salts thereof.
 3. A method of treating a patient suffering from, orsusceptible to pain by administration of an effective amount of acompound of formula (I)

and salts thereof.